Experimental spinal cord injury (SCI) models have helped define levels of structural and functional plasticity within the spinal cord and affected muscles. Exercise of hind limb muscles maintains the membrane properties of motoneurons affected by SCI, diminishes muscle atrophy and restores the H-reflex to near normal activity. Exercise-induced increase of neurotrophic factors (NTFs) in both spinal cord and muscle is correlated with neuromuscular plasticity. Intraspinal transplants of BDNF-producing fibroblasts indicate that therapeutic interventions also act at regions distant from the injury site. This study seeks to define structural and functional changes in spinal cord circuitry that occur after SCI and their modifications by exercise and/or transplantation to identify conditions that will lead to local and long distance anatomical and physiological recovery.
Aim 1 will address the hypothesis that exercise and/or transplants promote plasticity within the spinal cord that can be harnessed to enhance functional repair. We will use an adult rat transection injury to define histological, cellular and molecular changes in spinal cord after removal of all descending motor input and after single or combined treatments.
Aim 2 will determine if acute interventions affecting changes in spinal cord circuitry are effective when treatment is delayed.
Aim 3 will examine the possibility that exercise will promote axonal regrowth into the spinal cord distal to an injury and that neurotrophic factor upregulation is involved. A peripheral nerve graft will be used to direct regenerating axons to a distant target and evaluation of functional recovery will be followed by tract tracing procedures to define an anatomical basis for improvement.
In Aim 4 we will test the hypothesis that defects in neuromuscular connections post-SCI can be limited by exercise and/or transplantation. Anatomical and physiological measures of stability of neuromuscular junctions (NMJs) will be employed to assess the effectiveness of these 2 interventions. Differences of NMJ stability with short (2 week) and long (8 week) delay between SCI and treatment will demonstrate possible """"""""windows of opportunity"""""""" for reversing injury-induced changes in neuromuscular organization. Overall, these experiments will provide fundamental information about cellular and molecular aspects of spinal cord and muscle reorganization in acute and chronic stages of SCI that will be instrumental in designing strategies for repair.
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